Alzheimer's disease is a disease characterized by the degeneration or deciduation of nerve cells as well as the formation of senile plaques and the change of neurofibrils. The treatment of Alzheimer's disease is currently limited to symptomatic therapy using a symptom-improving agent exemplified by an acetylcholinesterase inhibitor; a basic therapeutic agent inhibiting the progression of the disease has not been developed. For creating a causal therapeutic agent for Alzheimer's disease, a method for controlling the pathogenesis of the disease state needs to be developed.
Aβ protein, a metabolic product of amyloid precursor protein (hereinafter referred to as APP), is thought to be significantly involved in the degeneration and deciduation of nerve cells and further the onset of dementia symptoms (see, for example, non-patent documents 1 and 2). The major components of Aβ protein are Aβ40 consisting of 40 amino acids and Aβ42 containing additional 2 amino acids. It is known that the Aβ40 and Aβ42 have high aggregability (see, for example, non-patent document 3) and are major constituents of the senile plaque (see, for example, non-patent documents 3, 4, and 5) and further that mutations in APP and presenilin genes seen in familial Alzheimer's disease increase the Aβ40 and Aβ42 (see, for example, non-patent documents 6, 7, and 8). Thus, a compound reducing the production of Aβ40 and Aβ42 is expected as an agent inhibiting the progression of, or preventing Alzheimer's disease.
Non-patent document 1: Klein W L and 7 coauthors, Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss, Proceeding National Academy of Science USA, 2003, Sep. 2; 100(18): 10417-10422.
Non-patent document 2: Nitsch R M and 16 coauthors, Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 38: 547-554.
Non-patent document 3: Jarrett J T and 2 coauthors, The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimers' disease, Biochemistry, 1993, 32(18): 4693-4697.
Non-patent document 4: Glenner G G and 1 coauthor, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and biophysical research communications, 1984, May 16, 120(3): 885-890.
Non-patent document 5: Masters C L and 5 coauthors, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, 1985, June, 82(12): 4245-4249.
Non-patent document 6: Gouras G K and 11 coauthors, Intraneuronal Aβ42 accumulation in human brain, American Journal of Pathology, 2000, January, 156(1): 15-20.
Non-patent document 7: Scheuner D and 20 coauthors, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, August, 2(8): 864-870.
Non-patent document 8: Forman M S and 4 coauthors, Differential effects of the swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and nonneuronal cells, The Journal of Biological Chemistry, 1997, Dec. 19, 272(51): 32247-32253.